Heavy drinking smokers constitute an important group of treatment resistant individuals. The study proposed herein seeks to add a neuroimaging component to the ongoing pharmacotherapy project in order to elucidate the neural basis of response to promising pharmacotherapies for smoking cessation in heavy drinkers. We propose to enroll a subset (n = 40;10 participants from each medication condition) of heavy drinking smokers randomized to one of the following four medication conditions: (1) varenicline (1 mg twice per day) alone;(2) naltrexone (25 mg once per day) alone;(3) varenicline + naltrexone;and (4) placebo. Participants will be matched on gender, alcohol use, and nicotine dependence severity. The proposed neuroimaging session will assess brain activity in response to smoking and alcohol cues. Based on previous research in this area, we propose to examine the following regions of interest (ROI): striatum, ventral tegmental area / substantia nigra (VTA / SN), orbitofrontal cortex (OFC), medial prefrontal cortex (MPFC), and insula. The neuroimaging paradigms proposed herein will allow us to elucidate the pathways and functional neuroanatomy underlying the effects of a promising combination of pharmacotherapies for smoking cessation. The objective of this program of research is to optimize smoking cessation for heavy drinking smokers, a sizeable and treatment resistant subgroup of smokers. PUBLIC HEALTH RELEVANCE: Heavy drinking smokers constitute an important group of treatment resistant individuals. The proposed study seeks to add a neuroimaging component to an ongoing study of combined medications for heavy drinking smokers in order to elucidate the neural basis of medication response. The proposed work aims to optimize smoking cessation for heavy drinking smokers, a sizeable and treatment resistant subgroup of smokers.